AB0386 ANALYSIS OF THE RELATIONSHIP BETWEEN THE METHOTREXATE PHARMACOKINETIC PARAMETERS AND RESPONSE TO METHOTREXATE THERAPY IN RHEUMATOID ARTHRITIS
Authors: G. Gridneva, E. Aronova, E. Samarkina, S. Glukhova, Y. Muraviev, N. Baymeeva
Journal: Annals of the Rheumatic Diseases (2022)

Background The key link in the therapeutic drug monitoring of methotrexate (MTX) is the measurement of the concentrations of its most stable metabolites, as well as products of the early and late stages of MTX conversion (short-chain polyglutamates). Metabolic rate of MTX can depend on the clinical characteristics of patients and concomitant drug therapy. Objectives To reveal the regularity of the distribution of various metabolites in patients who responded and did not respond to MTX therapy. To compare groups of patients with different responses to MTX according to clinical characteristics. Methods The study included 79 RA diagnosis according to ACR/EULAR 2010 criteria, 65 (82%) women and 14 (18%) men, aged 53 ± 11 years, naiive to MTX. All patients had normal renal excretory function (GFR more than 60 ml / min). All patients were prescribed MTX of 10-15 mg/m2 of body surface. Achievement of therapy targets was established according to the EULAR therapy response criteria. The determination of MTX monoglutamate in erythrocytes (ER) and mononuclear cells (MO), as well as the main metabolites of MTX-polyglutamates with 2,3 and 4 glutamate residues (MTXPG 2-4), as well as 7-hydroxymethotrexate (7-OH-MTX) was measured by the tandem chromatomass spectrometry after 4, 12 and 24 weeks of therapy, the result was expressed in nmol/L. The calculation was performed using the statistical data analysis package Statistica 10 for Windows (StatSoft Inc., USA) using the methods of parametric and nonparametric statistics. Results By the 24th week of therapy, 34 (43%) (group 1) patients achieved the targets of therapy, 36 (46%) did not achieve (group 2). MTX withdrawn in 5 (6%) patients - due to adverse reactions. 4 (5%) were unable to continue to participate due to SARS-CoV2 pandemic. After 4 weeks of treatment, the concentration of various MTX metabolites did not differ in the groups. After 12 weeks of therapy, significant differences were found in the content of 7-OH MTX in the ER: 28.19 [7.28;58.07] and 5.89 [0.79;20.03], respectively (p=0.002); the concentration of the remaining fractions did not differ. Group 1 showed a higher concentration of 7-OH-MTX in MO after 24 weeks of therapy - 5.23 [1.39;12.52] and 1.05 [0.07;3.55], respectively (p = 0.006). No differences between the concentrations of other MTX metabolites were found. The groups were matched for age, body mass index, duration of RA, and disease activity at the baseline. In group 2, patients used statins more often (2 (6%) versus 6 (37%), p = 0.01), however, there were no statistically significant differences in the concentration of MTX metabolites in the groups of patients taking and not taking statins. Conclusion The concentration of 7-OH-MTX after 12 and 24 weeks of therapy is statistically higher in the group of patients who responded to therapy. 7-OH-MTX appears to be a more persistent metabolite of MTX, therefore, it is more applicable for therapeutic drug monitoring of MTX. Patients taking statins may be potential nonresponders to MTX therapy. Disclosure of Interests None declared